Composition for eradicating Helicobacter pylori containing zastaprazan or a pharmaceutically acceptable salt thereof

Abstract

The present invention discloses a composition for eradicating Helicobacter pylori, which contains zastaprazan or a pharmaceutically acceptable salt thereof.

Description

[Technical Field]

[0001] The present invention relates to a composition for eradicating Helicobacter pylori, which comprises zastaprazan or a pharmaceutically acceptable salt thereof, and more particularly to a composition for eradicating Helicobacter pylori, which comprises zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, amoxicillin, a pharmaceutically acceptable salt thereof, or a hydrate thereof, and clarithromycin or a pharmaceutically acceptable salt thereof. [Background technology]

[0002] Helicobacter pylori (H. pylori) is a spiral-shaped gram-negative bacterium that lives in the human gastric mucosa. It is designated as a Class 1 carcinogen by the World Health Organization (WHO) and is a bacterium that infects approximately half of Korean adults. Helicobacter pylori (H. pylori) is a bacterium that parasitizes the gastric mucosa and continues to multiply, and will never disappear unless proper treatment is received.

[0003] The route of infection for Helicobacter pylori (H. pylori) is still unclear, but it is said to be transmitted from person to person. It is understood to be closely related to lifestyle habits unique to Korea, which exposes people to the risk of infection with Helicobacter pylori (H. pylori).

[0004] Helicobacter pylori (H. pylori) has been identified as a cause of atrophic gastritis, intestinal metaplasia, peptic ulcers, gastric mucosa-associated lymphoid tissue (MALT) lymphoma, and gastric cancer, and is also known to be associated with functional dyspepsia, iron deficiency anemia of unknown etiology, and chronic idiopathic thrombocytopenia.

[0005] A serological prevalence study of asymptomatic Korean adults in Japan conducted in a multi-institutional study showed that the rate was 51.0% in 2015, a steady decline compared to the past. This is attributed not only to aggressive treatment, but also to improved economic levels and sanitary conditions.

[0006] The primary eradication of Helicobacter pylori (H. pylori) involves taking a gastric acid suppressant and two antibiotics (amoxicillin and clarithromycin) for 14 days. The success rate of treatment is 70-80%, but some patients voluntarily discontinue treatment, resulting in treatment failure. In these patients, treatment may become difficult due to resistant strains.

[0007] The enzymes responsible for the pathogenesis of Helicobacter pylori (H. pylori) not only neutralize gastric acid, allowing Helicobacter pylori (H. pylori) to establish and grow in a highly acidic environment, but also the ammonia produced as a result of the enzyme's action affects gastric epithelial cells, and the various cytokines produced when Helicobacter pylori (H. pylori) stimulates gastric epithelial cells serve to attract various inflammatory cells.

[0008] Therefore, there is a strong need for the development of a treatment method that involves the combination of a new therapeutic agent that can exert direct antibacterial action against Helicobacter pylori (H. pylori) or inhibit the enzymes that degrade it, along with the antibiotics amoxicillin and clarithromycin. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] Republic of Korea Publication Patent No. 10-2000-0005291 Summary of the Invention [Problem to be solved by the invention]

[0010] The inventors of the present invention have recognized the need for the development of a composition for eradicating Helicobacter pylori (H. pylori) by combining amoxicillin and / or clarithromycin with a novel therapeutic agent capable of exerting a direct antibacterial or protease-inhibiting effect against H. pylori. Therefore, they have adopted zastaprazan, its pharmaceutically acceptable salt, a hydrate or solvate thereof, or a mixture thereof as a novel therapeutic agent capable of exerting a direct antibacterial or protease-inhibiting effect against H. pylori. They have confirmed that when used in combination with amoxicillin and / or clarithromycin, the synergistic and complementary effects of the combination significantly enhance the activity in eradicating H. pylori, and have therefore aimed to provide a novel two- or three-drug combination eradication composition. [Means for solving the problem]

[0011] In order to achieve the above object, the present invention discloses the following means.

[0012] In one aspect, the present invention discloses a composition for eradicating Helicobacter pylori, comprising zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, and amoxicillin, a pharmaceutically acceptable salt thereof, or a hydrate thereof.

[0013] In another aspect, the present invention discloses a composition for eradicating Helicobacter pylori, comprising zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, and clarithromycin or a pharmaceutically acceptable salt thereof.

[0014] In a final aspect, the present invention discloses a composition for eradicating Helicobacter pylori, comprising zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, amoxicillin, a pharmaceutically acceptable salt thereof, or a hydrate thereof, and clarithromycin or a pharmaceutically acceptable salt thereof. [Effects of the Invention]

[0015] The eradication composition of the present invention has a therapeutic effect on gastroesophageal reflux disease and / or peptic ulcers, regardless of whether or not a patient is infected with Helicobacter pylori (H. pylori), due to the Helicobacter pylori (H. pylori) eradication effect of zastaprazan, its pharmaceutically acceptable salt, their hydrate or solvate, or a mixture of these. It is particularly advantageous in that it is highly effective in patients infected with Helicobacter pylori (H. pylori), and that evaluation of all symptoms caused by Helicobacter pylori (H. pylori) infection (heartburn, acid reflux, heartburn / acid reflux) shows a tendency for all symptoms to improve within 24 hours and for 7 days.

[0016] Furthermore, the synergistic effect associated with the combined administration of zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof with amoxicillin, a pharmaceutically acceptable salt thereof, a hydrate thereof, or clarithromycin or a pharmaceutically acceptable salt thereof, results in excellent efficacy in eradicating Helicobacter pylori (H. pylori).

[0017] In addition, the pharmacokinetics (PK) of zastaprazan, its pharmaceutically acceptable salt, their hydrate or solvate, or a mixture thereof administered in combination with amoxicillin, its pharmaceutically acceptable salt, or their hydrate, and clarithromycin or its pharmaceutically acceptable salt was compared to the administration of zastaprazan, its pharmaceutically acceptable salt, their hydrate or solvate, or a mixture thereof alone in clinical trials. T This has the effect of increasing the efficiency by more than two times.

[0018] That is, the disinfecting effect of zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof itself, the synergistic effect of zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof with amoxicillin, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or clarithromycin or a pharmaceutically acceptable salt thereof, and the synergistic effect of zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof with amoxicillin, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or clarithromycin or a pharmaceutically acceptable salt thereof. Considering the pharmacokinetic (PK) results associated with the combined administration of zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, amoxicillin, a pharmaceutically acceptable salt thereof, or a hydrate thereof, and clarithromycin or a pharmaceutically acceptable salt thereof, there is a synergistic effect in eradicating Helicobacter pylori (H. pylori) with the combined use of three drugs: zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, amoxicillin, a pharmaceutically acceptable salt thereof, or a hydrate thereof, and clarithromycin or a pharmaceutically acceptable salt thereof.

[0019] The effects of the present invention are not limited to those described above, but may include a wide variety of effects within a range that is obvious to a person skilled in the art from the content described below. DETAILED DESCRIPTION OF THE INVENTION

[0020] This specification will be explained in more detail below.

[0021] This will be explained in detail as follows. The terms used in this specification have been selected as widely used as possible, taking into consideration the functions of the present invention. However, this may vary depending on the intentions of engineers in the field, legal precedents, the emergence of new technologies, etc. In certain cases, the applicant may arbitrarily select terms, and in such cases, their meanings will be described in detail in the section describing the invention. Therefore, the terms used in this specification should not be simply defined by their names, but should be defined in light of the meanings of the terms and the overall content of the present invention.

[0022] Furthermore, unless otherwise specified herein or clearly contradicted by the context, all terms used in this disclosure, including technical and scientific terms, have the same meaning as commonly understood by a person of ordinary skill in the art to which this invention belongs. In addition, commonly used terms and dictionary-defined terms should be interpreted as having a meaning consistent with the meaning they have in the context of the relevant art, and should not be interpreted as an ideal meaning or an overly formal meaning unless clearly defined in this application.

[0023] Numerical ranges are inclusive of the numerical values ​​defined in the range. Every maximum numerical limitation given throughout this specification includes every lower numerical limitation, as if such lower numerical limitation were expressly written. Every minimum numerical limitation given throughout this specification includes every higher numerical limitation, as if such higher numerical limitation were expressly written. Every numerical limitation given throughout this specification is intended to include every better numerical range within the broader numerical range, as if such narrower numerical limitations were expressly written.

[0024] Each description and embodiment disclosed in the present invention below can be applied to other descriptions and embodiments related thereto. In other words, all combinations of the various elements disclosed in the present invention fall within the scope of the present invention. In addition, the scope of the present invention is not limited by the specific descriptions described below.

[0025] As used in this disclosure, terms such as "comprises," "having," "including," and "comprising" should be construed as open-ended terms (i.e., meaning "including, but not limited to") that include the possibility of including other embodiments, unless the phrase or sentence in which the term appears clearly indicates otherwise.

[0026] As used herein, zastaprazan may refer to zastaprazan, its pharmaceutically acceptable salt, a hydrate or solvate thereof, or a mixture thereof. Accordingly, as used herein, a pharmaceutical composition containing zastaprazan may refer to a composition containing zastaprazan, its pharmaceutically acceptable salt, a hydrate or solvate thereof, or a mixture thereof.

[0027] In this specification, amoxicillin may refer to amoxicillin, a pharmaceutically acceptable salt thereof, or a hydrate thereof. Therefore, in this specification, a pharmaceutical composition containing amoxicillin may refer to a composition containing amoxicillin, a pharmaceutically acceptable salt thereof, or a hydrate thereof.

[0028] Clarithromycin may refer to clarithromycin or a pharmaceutically acceptable salt thereof. Therefore, herein, a pharmaceutical composition containing clarithromycin may refer to a composition containing clarithromycin or a pharmaceutically acceptable salt thereof.

[0029] The present invention will be described in detail below.

[0030] Composition for eradicating Helicobacter pylori containing zastaprazan

[0031] The present invention discloses a composition for eradicating Helicobacter pylori, which comprises zastaprazan and amoxicillin.

[0032] Specifically, the present invention discloses a composition for eradicating Helicobacter pylori, which comprises zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, and amoxicillin, a pharmaceutically acceptable salt thereof, or a hydrate thereof.

[0033] The present invention discloses a composition for eradicating Helicobacter pylori, which comprises zastaprazan and clarithromycin.

[0034] Specifically, the present invention discloses a composition for eradicating Helicobacter pylori, which comprises zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, and clarithromycin or a pharmaceutically acceptable salt thereof.

[0035] The present invention discloses a composition for eradicating Helicobacter pylori, which comprises zastaprazan, amoxicillin, and clarithromycin.

[0036] Specifically, the present invention discloses a composition for eradicating Helicobacter pylori, which comprises zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, amoxicillin, a pharmaceutically acceptable salt thereof, or a hydrate thereof, and clarithromycin or a pharmaceutically acceptable salt thereof.

[0037] The eradication composition of the present invention contains the antibiotics amoxicillin, a pharmaceutically acceptable salt thereof, or a hydrate thereof, and / or clarithromycin or a pharmaceutically acceptable salt thereof, as well as zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof. Zastaprazan itself has the effect of eradicating Helicobacter pylori (H. pylori), thereby providing a therapeutic effect for gastroesophageal reflux disease and / or peptic ulcers. Zastaprazan is particularly advantageous in that it is highly effective in patients infected with Helicobacter pylori (H. pylori), and when evaluated within 24 hours / 7 days for all symptoms caused by H. pylori infection (heartburn, acid reflux, heartburn / acid reflux), all symptoms tend to improve within 24 hours and for 7 days.

[0038] Another eradication composition of the present invention uses zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof in combination with the antibiotic amoxicillin, a pharmaceutically acceptable salt thereof, a hydrate thereof, or clarithromycin or a pharmaceutically acceptable salt thereof (two-drug combination), and by using these in combination, the synergistic and complementary effects of the combination result in significantly increased activity in eradicating Helicobacter pylori (H. pylori).

[0039] Furthermore, still another disinfecting composition of the present invention uses zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof in combination with antibiotics amoxicillin, a pharmaceutically acceptable salt thereof, or a hydrate thereof, and clarithromycin or a pharmaceutically acceptable salt thereof (triple-drug combination), and by using these in combination, the AUC T This has the effect of increasing the rate by more than two times.

[0040] Through this, the disinfection effect of zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof itself, the synergistic effect of zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof with amoxicillin, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or clarithromycin or a pharmaceutically acceptable salt thereof, and the synergistic effect of zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof with amoxicillin are demonstrated. Considering the pharmacokinetic (PK) results associated with the combined administration of zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, amoxicillin, a pharmaceutically acceptable salt thereof, or a hydrate thereof, and clarithromycin or a pharmaceutically acceptable salt thereof, it is clear that there is a synergistic effect in eradicating Helicobacter pylori (H. pylori) when the three-drug combination is administered in combination with zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, amoxicillin, a pharmaceutically acceptable salt thereof, or a hydrate thereof, and clarithromycin or a pharmaceutically acceptable salt thereof.

[0041] In the present invention, zastaprazan is an active ingredient for eradicating Helicobacter pylori (H. pylori).

[0042] In the present invention, the term "active ingredient" refers to a substance or group of substances, including a main ingredient or an effective ingredient, that are expected to directly or indirectly exert the efficacy and effect of the pharmaceutical composition through their inherent pharmacological action.

[0043] In the present invention, zastaprazan is an example of an imidazo[1,2-a]pyridine derivative, and its chemical name is azetidin-1-yl-[8-[2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl]methanone.

[0044] Zastaprazan of the present invention may exist in the form of a pharmaceutically acceptable salt, and acid addition salts formed with a pharmaceutically acceptable free acid are useful as the salt. In the present invention, the term "pharmaceutically acceptable salt" refers to any and all organic or inorganic acid addition salts of zastaprazan that are relatively non-toxic to patients and have an innocuous effective concentration, and the side effects attributable to the salt do not reduce the beneficial efficacy of zastaprazan. The free acid may be an organic or inorganic acid. Examples of inorganic acids that may be used include hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, and stannic acid. Examples of organic acids that may be used include methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carboxylic acid, vanillic acid, and hydroiodic acid.

[0045] The pharmaceutically acceptable salts of the present invention include salts of acidic or basic groups that may be present in zastaprazan, unless otherwise specified. For example, pharmaceutically acceptable salts include sodium, calcium, and potassium salts of hydroxy groups, and other pharmaceutically acceptable salts of amino groups include hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate), and p-toluenesulfonate (tosylate) salts, which can be prepared by salt preparation methods well known in the art.

[0046] Specifically, the pharmaceutically acceptable salt of zastaprazan may be zastaprazan citrate salt (azetidin-1-yl{8-[2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate salt), but the present invention is not limited thereto.

[0047] In the present invention, the term "hydrate" refers to a compound in which the active ingredient zastaprazan or a pharmaceutically acceptable salt thereof is bound to water by non-covalent intermolecular forces, and contains a stoichiometric or non-stoichiometric amount of water. Specifically, the hydrate may contain water in a molar ratio of about 0.25 to about 10 moles per mole of the active ingredient, more specifically, about 0.5 moles, about 1 mole, about 1.5 moles, about 2 moles, about 3 moles, or about 5 moles, etc.

[0048] In the present invention, the term "solvate" means a compound in which the active ingredient zastaprazan or a pharmaceutically acceptable salt thereof and a solvent are bound by non-covalent intermolecular forces, and which contains a stoichiometric or non-stoichiometric amount of the solvent. A suitable solvent is volatile, non-toxic, and can be administered to humans in extremely small amounts. Examples of the solvate include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-acetate, acetone, acetic acid, anisole, tetrahydrofuran, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, isobutyl acetate, n-butyl acetate, dimethyl sulfoxide, pentane, and heptane, but the solvate of the present invention is not limited to these examples. Specifically, the solvate may contain water in a molar ratio of about 0.25 to about 10 moles per mole of the active ingredient, and more specifically, the solvate may contain about 0.5 moles, about 1 mole, about 1.5 moles, about 2 moles, about 3 moles, or about 5 moles, etc.

[0049] In the present invention, the term "eradication" has almost the same meaning as sterilization, meaning the removal of bacteria. It refers to a state in which microorganisms are not killed directly but are destroyed after a certain period of time by stopping their metabolism, i.e., a state in which the proliferation and growth of bacteria are stopped. In the present invention, eradication of Helicobacter pylori (H. pylori) can be said to include the removal or eradication of Helicobacter pylori (H. pylori) present in the human stomach, and the cessation of the proliferation and growth of Helicobacter pylori (H. pylori).

[0050] In the present invention, the composition can be administered once to three times a day, preferably once or twice a day. Specifically, the zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, amoxicillin, a pharmaceutically acceptable salt thereof, a hydrate thereof, and / or clarithromycin or a pharmaceutically acceptable salt thereof can be administered once to three times a day, preferably once or twice a day, for 5 to 14 days, although the present invention is not limited thereto.

[0051] In the present invention, zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof may contain 1 mg to 100 mg, 2 mg to 60 mg, or 3 mg to 40 mg of zastaprazan (in the form of the free base), specifically, about 3.3, 6.6, 13.1, 26.2, or 52.4 mg of zastaprazan (in the form of the free base), and may contain 5 to 40 mg of zastaprazan citrate salt, specifically, 5 mg, 10 mg, 15 mg, 20 mg, or 40 mg of zastaprazan citrate salt, more specifically, 10 mg, 20 mg, or 40 mg of zastaprazan citrate salt. Thus, even though the composition of the present invention contains a low dose (10 mg or 20 mg) of zastaprazan, it has the same or greater efficacy in eradicating Helicobacter pylori (H. pylori) as 40 mg Nexium tablets, demonstrating a high cure rate and improving symptoms such as heartburn, acid reflux, and heartburn / acid reflux within 24 hours and for 7 days after administration. Furthermore, even though the composition contains a low dose of zastaprazan, it has the advantage of significantly enhancing its activity in eradicating Helicobacter pylori (H. pylori) due to the synergistic and complementary effects achieved when used in combination with amoxicillin, a pharmaceutically acceptable salt thereof, or a hydrate thereof, and / or clarithromycin or a pharmaceutically acceptable salt thereof.

[0052] In the present invention, amoxicillin, a pharmaceutically acceptable salt thereof, or a hydrate thereof may be contained in an amount of 100 mg to 1000 mg, specifically, 375 mg to 625 mg, and more specifically, 500 mg, but the present invention is not limited thereto.

[0053] In the present invention, clarithromycin or a pharmaceutically acceptable salt thereof may be contained in an amount of 100 mg to 1000 mg, specifically 125 mg to 875 mg, and more specifically 500 mg, but the present invention is not limited thereto.

[0054] In the present invention, the contents regarding pharmaceutically acceptable salts and hydrates of amoxicillin and clarithromycin are loosely defined as those explained above regarding zastaprazan.

[0055] In the present invention, the disinfecting composition may contain one or more pharmaceutical additives including an excipient, a disintegrant, a binder, and a lubricant, but the present invention is not limited thereto.

[0056] In the present invention, the excipient may be one or more of microcrystalline cellulose, lactose hydrate, anhydrous lactose, sucrose, D-mannitol, starch, corn starch, and hard anhydrous silicic acid, but the present invention is not limited thereto.

[0057] In the present invention, examples of the disintegrant include starches or modified starches such as sodium starch glycolate, corn starch, potato starch, or pregelatinized starch; clays such as bentonite, montmorillonite, or veegum; celluloses such as hydroxypropyl cellulose or carboxymethyl cellulose; algins such as sodium alginate or alginic acid; cross-linked celluloses such as croscarmellose sodium; gums such as guar gum and xanthan gum; cross-linked polymers such as crospovidone; and anisotropic preparations such as sodium bicarbonate and citric acid. These may be used alone or in combination, and the present invention is not limited thereto.

[0058] In the present invention, the binder may be at least one selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, copovidone, starch, microcrystalline cellulose, colloidal silicon dioxide, mannitol, lactose, polyethylene glycol, and mixtures thereof, but the present invention is not limited thereto.

[0059] In the present invention, examples of the lubricant include calcium stearate, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate, zinc stearate, stearic acid, hardened vegetable oil, polyethylene glycol, sodium benzoate, talc, etc. These may be used alone or in combination of two or more, and the present invention is not limited thereto.

[0060] In the present invention, the disinfecting composition may be a solid oral preparation, but the present invention is not limited thereto.

[0061] In the present invention, the solid oral preparation may be any one of tablets, film-coated tablets, capsules, powders, granules, pills, lozenges, oral jellies, and orally dissolving films, but the present invention is not limited thereto.

[0062] In particular, in the case of film-coated tablets, coating bases well known in the art can be used, and the present invention is not limited thereto.

[0063] Pharmaceutical composition containing zastaprazan for treating Helicobacter pylori infection

[0064] The present invention discloses a composition for treating Helicobacter pylori infection, comprising zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, and amoxicillin, a pharmaceutically acceptable salt thereof, or a hydrate thereof.

[0065] The present invention discloses a composition for treating Helicobacter pylori infection, comprising zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, and clarithromycin or a pharmaceutically acceptable salt thereof.

[0066] The present invention discloses a composition for treating Helicobacter pylori infection, comprising zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, amoxicillin, a pharmaceutically acceptable salt thereof, or a hydrate thereof, and clarithromycin or a pharmaceutically acceptable salt thereof.

[0067] Zastaprazan is as described above.

[0068] In the present invention, the term "treatment" means partially or completely alleviating, ameliorating, mitigating, inhibiting or delaying the development of Helicobacter pylori, reducing the severity or reducing the occurrence of one or more symptoms or characteristics thereof, by administering a composition of the present invention.

[0069] The above-mentioned contents regarding the disinfecting composition are all applicable to the composition for treating infections, unless they are inconsistent with each other.

[0070] A method for eradicating Helicobacter pylori, comprising administering a pharmaceutical composition to a subject in need thereof.

[0071] The present invention provides a method for eradicating Helicobacter pylori, which comprises the step of administering to a subject in need thereof a pharmaceutically effective amount of a composition comprising zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, and amoxicillin, a pharmaceutically acceptable salt thereof, or a hydrate thereof.

[0072] The present invention provides a method for eradicating Helicobacter pylori, which comprises the step of administering to a subject in need thereof a pharmaceutically effective amount of a composition comprising a therapeutically effective amount of zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, and clarithromycin or a pharmaceutically acceptable salt thereof.

[0073] The present invention provides a method for eradicating Helicobacter pylori, which comprises the step of administering to a subject in need thereof a pharmaceutically effective amount of a composition containing a therapeutically effective amount of zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, amoxicillin, a pharmaceutically acceptable salt thereof, or a hydrate thereof, and clarithromycin or a pharmaceutically acceptable salt thereof.

[0074] In the present invention, the term "pharmaceutically effective amount" refers to an amount effective for eradicating Helicobacter pylori, including, for example, an amount of a composition administered to a subject that prevents the occurrence or recurrence of Helicobacter pylori, alleviates symptoms, inhibits direct or indirect pathological consequences, prevents metastasis, slows the rate of progression, alleviates or temporarily alleviates the condition, or improves prognosis. In other words, the pharmaceutically effective amount can be interpreted as encompassing any dose of the composition that can eradicate Helicobacter pylori.

[0075] Specifically, in the Helicobacter pylori eradication method of the present invention, zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof is administered to the subject once a day at 5 mg to 100 mg as zastaprazan (in the form of the free base), thereby preventing the recurrence of peptic ulcers induced by the administration of nonsteroidal anti-inflammatory drugs and preventing the onset of peptic ulcers. Specifically, 1 mg to 100 mg, 2 mg to 60 mg, or 3 mg to 40 mg of zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof as zastaprazan (free base form), specifically, about 3.3, 6.6, 13.1, 26.2, or 52.4 mg of zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof as zastaprazan (free base form), or 5 to 40 mg of zastaprazan citrate salt, preferably 5 mg, 10 mg, 15 mg, 20 mg, or 40 mg of zastaprazan citrate salt, can be administered to the subject once to three times a day to eradicate Helicobacter pylori and efficiently treat the subject.

[0076] In the present invention, the term "subject" refers to a mammal, and specifically, mammals including humans include mammals such as humans, monkeys, cows, horses, dogs, cats, rabbits, rats, and mice, and more specifically may refer to humans. However, the subject may also be a person infected or suspected of being infected with Helicobacter pylori due to gastroesophageal reflux disease, chronic gastritis, gastric or duodenal ulcers, stomach cancer, etc.

[0077] Here, "individuals infected with Helicobacter pylori" means individuals who have been confirmed to be infected with Helicobacter pylori through respiratory or stool tests or upper endoscopy due to symptoms such as gastroesophageal reflux symptoms (heartburn, acid reflux, heartburn / acid reflux, etc.), upper abdominal pain, indigestion, or abdominal discomfort (feeling of gas, heavy stomach, feeling of fullness in the stomach, bloating, or burning sensation), and "individuals suspected of being infected with Helicobacter pylori" means individuals experiencing any of the above symptoms.

[0078] The above-mentioned contents regarding the disinfecting composition are all applicable to the disinfecting method as long as they are not inconsistent with each other.

[0079] Use for eradicating Helicobacter pylori

[0080] The present invention provides a pharmaceutical composition comprising zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, and amoxicillin, a pharmaceutically acceptable salt thereof, or a hydrate thereof, for eradicating Helicobacter pylori.

[0081] The present invention provides use of a pharmaceutical composition comprising zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, and clarithromycin or a pharmaceutically acceptable salt thereof, for eradicating Helicobacter pylori.

[0082] The present invention provides use of a pharmaceutical composition comprising zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, amoxicillin, a pharmaceutically acceptable salt thereof, or a hydrate thereof, and clarithromycin or a pharmaceutically acceptable salt thereof, for eradicating Helicobacter pylori.

[0083] The above-mentioned contents regarding the eradication composition are all applicable to the use for eradicating Helicobacter pylori, unless they are inconsistent with each other.

[0084] Use for the manufacture of drugs for eradicating Helicobacter pylori

[0085] The present invention provides use of a composition comprising zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, and amoxicillin, a pharmaceutically acceptable salt thereof, or a hydrate thereof, for the manufacture of a medicament for eradicating Helicobacter pylori.

[0086] The present invention provides use of a composition comprising zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, and clarithromycin or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for eradicating Helicobacter pylori.

[0087] The present invention provides use of a composition comprising zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, amoxicillin, a pharmaceutically acceptable salt thereof, or a hydrate thereof, and clarithromycin or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for eradicating Helicobacter pylori.

[0088] The composition of the present invention for producing a medicament may be mixed with an acceptable carrier or the like, and may further contain other active ingredients.

[0089] The above-mentioned contents regarding the eradication composition are all applicable to the use for producing the Helicobacter pylori eradication drug unless they are inconsistent with each other.

[0090] The present invention will be described in more detail below using Production Examples and Examples. It will be obvious to those skilled in the art that these Production Examples and Examples are merely for the purpose of more specifically illustrating the present invention, and that the scope of the present invention is not limited thereto.

[0091] The active ingredient used in the following preparations and examples relates to zastaprazan citrate salt, which for convenience will be designated as zastaprazan or code name JP-1366.

[0092] Manufacturing example.

[0093] Production Example 1. Production of Zastaprazan Citrate Salt

[0094] Azetidin-1-yl{8-[2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate salt was obtained according to the following steps. Specifically, azetidin-1-yl{8-[2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone was obtained according to the procedure described in Korean Patent Publication No. 10-1777971. The nuclear magnetic resonance (NMR) analysis results of the azetidin-1-yl{8-[2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone obtained above are as follows:

[0095] 1 H NMR (400 MHz, CDCl3); δ7.63(d, J=1.2 Hz, 1H), 7.13(dd, J =8.4, 6.8 Hz, 1H), 7.06-7.04(m, 2H), 6.42(d, J= 1.2 Hz, 1H), 4.86-4.84(m, 1H), 4.41-4.28(m, 4H), 4.37(d, J =4.4 Hz, 2H), 3.75-3.69(m, 1H), 2.43-2.34(m, 13H).

[0096] Next, the azetidin-1-yl{8-[2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone obtained above was mixed with an alcohol solvent (isopropyl alcohol, IPA), stirred, and then vacuum-dried at approximately 30°C to 35°C to obtain a dried product. Approximately 10 g of this was taken and stirred with approximately 167 g of acetone. A solution of approximately 5 g of citric acid in approximately 33 g of acetone was gradually added dropwise over 60 minutes and stirred at the same temperature for 1 hour. The mixture was cooled to approximately 20°C to 25°C and further stirred for 1 hour. The resulting solid was filtered, washed with acetone, and vacuum-dried to obtain azetidin-1-yl{8-[2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate salt. The NMR analysis results of the azetidin-1-yl{8-[2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate salt (zastaprazan citrate salt) obtained above are as follows.

[0097] 1 H NMR(400MHz, MeOD); δ 7.90(s, 1H), 7.06-7.15(m, 3H), 6.77(s, 1H), 4.50(t, J=7.2Hz, 2H), 4.45(s, 2H), 4.24(t, J=7.2Hz, 2H), 2.80(d, J=15.6Hz, 2H), 2.70(d, J=12.0, 2H), 2.39-2.44(m, 11H), 2.35(s, 3H)

[0098] Manufacturing Example 2: Manufacturing of JP-1366 Capsules 5 mg (Zastaprazan Citrate Salt 5 mg)

[0099] A mixture was obtained by mixing 5 mg of azetidin-1-yl{8-[2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate salt (zastaprazan citrate salt) obtained according to Preparation Example 1, 220.8 mg of dimannitol, 13.0 mg of croscarmellose sodium, and 1.2 mg of magnesium stearate. The mixture was filled into hard capsules No. 1 using the capsule base to produce a capsule formulation.

[0100] The capsules thus produced are called "JP-1366 Capsules 5 mg."

[0101] Production Example 3: Production of JP-1366 tablets 20 mg (zastaprazan citrate salt 20 mg)

[0102] A mixture was obtained by mixing 20 mg of azetidin-1-yl{8-[2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate (zastaprazan citrate) obtained according to Preparation Example 1, 133.4 mg of microcrystalline cellulose, 6.4 mg of sodium stearyl fumarate, 40.0 mg of anhydrous lactose, 6.0 mg of croscarmellose sodium, and 4.2 mg of magnesium stearate. The mixture was directly compressed to obtain tablets. Subsequently, the tablets were coated with 8.0 mg of Opadry® 03B54445 pink to produce film-coated tablets.

[0103] The film-coated tablets thus produced are called "JP-1366 20 mg."

[0104] Manufacturing Example 4: Manufacturing of JP-1366 Capsules 20 mg (Zastaprazan Citrate Salt 20 mg)

[0105] A mixture was obtained by mixing 20 mg of azetidin-1-yl{8-[2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate (zastaprazan citrate) obtained according to Preparation Example 1, 181.4 mg of dimannitol, 12.4 mg of croscarmellose sodium, and 1.2 mg of magnesium stearate. The mixture was filled into hard capsules No. 1 using the capsule base to produce a capsule formulation.

[0106] The capsules thus produced are called "JP-1366 Capsules 20 mg."

[0107] Manufacturing Example 5. JP-1366 Capsules 20mg Placebo (Fake Drug)

[0108] Zastaprazan capsules 20 mg placebo were prepared in the same manner as in Preparation Example 4, except that zastaprazan citrate, the main ingredient, was not used. The capsules prepared in this manner are referred to as "JP-1366 capsules 20 mg placebo."

[0109] Example 1. Anti-Helicobacter pylori (H. pylori) in vitro efficacy test - Confirmation of the eradication effect of Zastaprazan itself

[0110] Experiments were conducted to confirm whether zastaprazan has the effect of inhibiting the growth of Helicobacter pylori (H. pylori) or suppressing the activity of its enzymes under in vitro experimental conditions.

[0111] 1. Test Substance

[0112] A. Drugs

[0113] The drugs used in the in vitro experiments are as shown in Table 1 below.

[0114] [Table 1]

[0115] A. Reagents

[0116] The reagents used in the in vitro experiments are as shown in Table 2 below.

[0117] [Table 2]

[0118] C. Bacterial strain

[0119] Helicobacter pylori (H. pylori) (ATCC43504): Reference strain for antibiotic susceptibility testing according to CLSI guidelines.

[0120] Helicobacter pylori (H. pylori) (ATCC700329): A strain isolated from a patient in the UK. It is a strain known to be associated with the development of gastric cancer, and is positive for the cytotoxin-associated gene (CagA) and vacuolating cytotoxin (VacA). Its genetic background is well known, and it is a strain primarily used for research purposes.

[0121] Helicobacter pylori (H. pylori) SS1 (mouse colonizing strain): Also known as the Sydney strain, this strain is CagA-positive and VacA-positive and has been shown to infect and colonize C57BL / 6 mice, and is used in animal experiments.

[0122] D. Equipment

[0123] The equipment used in the in vitro experiments is as shown in Table 3 below.

[0124] [Table 3]

[0125] 2. Culture Medium Preparation

[0126] A. Culture medium

[0127] Liquid medium was prepared using Brain Heart Infusion (BHI) (Difco, Sparks, MD, USA), 7% Differentiation Medium (horse serum, Sigma-Aldrich, St. Louis, MO, USA), and 0.4% Isovitalex™ (Baltimore Biological Laboratory, Sparks, MD, USA). Solid medium was prepared by adding 7% Laked Horse Blood (Oxoid, Basingstoke, Hampshire, UK), 0.4% Isovitalex, and 1.5–2% Bacto-agar (Difco, Sparks, MD, USA) to BHI.

[0128] A. Medium for measuring minimum inhibitory concentration (MIC)

[0129] The medium was prepared using Muller Hinton broth (MH) (Difco, Sparks, Maryland, USA) [w / 7% differentiation medium (Sigma-Aldrich, St. Louis, Missouri, USA), 0.4% Isovitalex (Baltimore Biological Laboratory, Sparks, Maryland, USA)].

[0130] 3. In-vitro efficacy study - Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of Zastaprazan (JP-1366) against Helicobacter pylori

[0131] ( 1) Method

[0132] Antibiotic susceptibility testing was performed using the microdilution method in accordance with CLSI guidelines. Amoxicillin and clarithromycin were serially diluted in 2-fold increments, with the highest concentration being 128 μg / mL, and omeprazole was diluted in 12-fold increments, with the highest concentration being 256 μg / mL. A positive control group was created by inoculating bacteria into wells containing only medium without antibiotics, while a negative control group was created by inoculating bacteria into wells containing only medium without antibiotics or bacteria. The concentration ranges of the test substances, zastaprazan (JP-1366) and fexuprazan, were determined through preliminary experiments. Helicobacter pylori (H. pylori) stored in a deep freezer (below -70°C) is thawed and inoculated onto BHI agar (w / 7% hemolyzed horse blood, 0.4% Isovitalex) and cultured at 37°C under microaerophilic conditions of 5% O2, 10% CO2, and 85% N2 gas for 3 days, after which it is subcultured onto new medium. The cultured bacteria are harvested and suspended in phosphate-buffered saline (PBS) and then subcultured at 5 x 10 5 Each well was inoculated with a concentration of 1000 cfu / mL of bacteria, and incubated at 37°C under microaerophilic conditions of 5% O2, 10% CO2, and 85% N2 for 3 days. The lowest concentration at which no bacterial growth was observed was determined as the minimum inhibitory concentration (MIC). Ten microliters of the culture medium from each well was then spotted onto antibiotic-free BHI agar (with 7% hemolyzed horse blood, 0.4% Isovitalex) and incubated at 37°C under microaerophilic conditions for 3 days. The lowest concentration at which no bacterial growth was observed was determined as the minimum bactericidal concentration (MBC).

[0133] ( 2) Experimental results and analysis

[0134] MIC determination involves visual inspection and measuring absorbance at 600 nm to confirm growth relative to the absorbance of the negative control group containing only medium. MBC determination involves spotting 10 μl of culture medium from each well onto solid medium containing no antibiotic or test substance, and then confirming bacterial growth.

[0135] The suitability of this test system is measured by the MIC value of amoxicillin against the reference strain Helicobacter pylori (H. pylori) ATCC43504, and the degree of control is determined at the result level.

[0136] All tests are carried out in duplicate and the results are determined by repeating the experiment three times.

[0137] As shown in Table 4 below, zastaprazan (JP-1366) has low solubility, making MIC analysis difficult (poor solubility, generation of suspension, and generation of interference in visual / absorbance analysis). Therefore, the inhibitory effect against Helicobacter pylori (H. pylori) strains was confirmed using the MBC index.

[0138] In the case of the test substance, zastaprazan (JP-1366), the inhibitory effect on three strains of Helicobacter pylori (H. pylori) was found to be at least 2 to at most 16 times more effective than omeprazole and fexprazan in the case of MBC.

[0139] [Table 4]

[0140] Example 2. Anti-Helicobacter pylori (H. pylori) efficacy study (Phase II clinical trial) in patients with erosive gastroesophageal reflux disease - Confirmation of the eradication effect of zastaprazan itself

[0141] 1. Selection of subjects

[0142] Helicobacter pylori (H. pylori) testing

[0143] Helicobacter pylori (H. pylori) testing was confirmed by one of the following methods: 13C-iodine aerobic testing (13C-UBT), gastroscopy (CLO), or histology. Testing was performed at the screening visit (Visit 1) or randomization visit (Visit 2). Results available within 29 days at the same institution prior to the randomization visit (Visit 2) could be used to confirm H. pylori positivity or negativity.

[0144] Selection criteria

[0145] Unless otherwise specified, subjects must meet all of the following selection criteria to participate in this clinical trial.

[0146] 1) Adult men and women who are 19 years of age or older and under 75 years of age as of the date of written consent

[0147] 2) Subjects who experienced heartburn or acid reflux within 7 days prior to the screening visit (Visit 1)

[0148] [Table 5]

[0149] 3) Subjects who have been diagnosed with erosive gastroesophageal reflux disease (GERD) of grade A or higher according to the Los Angeles Classification (LA Classification) on upper gastrointestinal endoscopy at the same institution within 29 days prior to the randomization visit (Visit 2).

[0150] [Table 6]

[0151] 4) Those who can fill out questionnaires and write test subject diaries.

[0152] 5) Subjects who have given written consent to participate in this clinical trial

[0153] Exclusion criteria

[0154] Patients who met any one of the following criteria were excluded from this clinical trial.

[0155] 1) Excluded diseases

[0156] (1) Patients with Barrett's esophagus >3 cm or significant dysplastic changes on upper gastrointestinal endoscopy at the time of screening visit (Visit 1)

[0157] (2) Eosinophilic esophagitis (However, cases where esophageal biopsy results are negative can also be included.)

[0158] (3) Subjects with primary esophageal motility disorder or esophageal stenosis

[0159] (4) Gastroesophageal varices

[0160] (5) Subjects who have gastrointestinal bleeding or other abnormal bleeding on upper gastrointestinal endoscopy at the time of the screening visit (Visit 1).

[0161] (6) Those who have undergone gastric acid suppression surgery or gastroesophageal surgery. However, if any of the following applies, registration is possible.

[0162] [1] Appendectomy, cholecystectomy, polypectomy

[0163] [2] In the case of endoscopic resection of malignant tumors or early gastric cancer endoscopic resection (EMR, ESD), if the patient is cured and has had no recurrence for more than 5 years since the date of diagnosis.

[0164] (7) Those who currently have active adult duodenal ulcer, gastric ulcer, or pancreatitis

[0165] (8) Zollinger-Ellison syndrome

[0166] (9) Subjects with irritable bowel syndrome (IBS) or inflammatory bowel disease (IBD)

[0167] (10) Subjects who, in the examiner's judgment, have warning symptoms that suggest a malignant disease of the gastrointestinal tract (e.g., pain when swallowing, severe difficulty in swallowing, bleeding, weight loss, anemia, bloody stool, etc.) (However, subjects may be enrolled if the presence or absence of a tumor is confirmed by endoscopic examination of the upper gastrointestinal tract and the result is negative).

[0168] 2) Past medical history and accompanying illnesses

[0169] (1) Subjects with clinically significant liver, kidney, nervous system, respiratory system, endocrine system, hematologic tumor, cardiovascular system, or urinary system disease

[0170] (2) Those with a history of malignant tumors within the five years prior to the screening visit (Visit 1). (However, those who have been cured and have not had a recurrence for more than five years since the date of diagnosis are eligible to enroll. However, those with a history of malignant tumors of the digestive system or tumor resections (e.g., gastric resection, colectomy, etc.) other than those who fall under (1) to (6) are not eligible to enroll.)

[0171] (3) Those who have had a history of alcohol or drug abuse within the year prior to the screening visit (Visit 1).

[0172] (4) Those with a history of human immunodeficiency virus (HIV)

[0173] (5) Persons diagnosed with a psychiatric disorder that may affect the progress of this clinical trial (e.g., schizophrenia, dementia)

[0174] 3) Actual laboratory test results (at the time of screening visit)

[0175] (1) Subjects whose serum AST, ALT, ALP, γ-GT or total bilirubin levels are more than twice the upper limit of normal

[0176] (2) Subjects whose serum BUN or serum creatinine levels are more than twice the upper limit of normal

[0177] (3) Active hepatitis B or C (can be registered if the virus is not detected).

[0178] 4) Drug Ability / Treatment Ability

[0179] (1) Individuals who are taking or are expected to take drugs that are prohibited from concomitant use during the clinical trial period

[0180] 5) History of hypersensitivity reactions

[0181] (1) Patients with a history of hypersensitivity to the components of Nexium tablets (esomeprazole) or benzimidazoles, phenicillin antibiotics, or macrolide antibiotics.

[0182] 6) Other

[0183] (1) Pregnant women, lactating women, women who have tested positive for pregnancy, or women or men of childbearing age who are planning to become pregnant during the clinical trial period

[0184] (2) If the female subject and the female partner of the male subject are women of childbearing age who have not undergone sterilization surgery, they will not agree to use the following contraceptive methods during the clinical trial period.

[0185] (3) Subjects who have received other clinical trial drugs within one month prior to the screening visit (Visit 1)

[0186] (4) Any person other than those mentioned above who the investigator determines is not suitable to participate in this clinical trial.

[0187] 2. Clinical trial method

[0188] This clinical trial is a randomized, double-blind, active-controlled, multi-center, Phase II clinical trial targeting patients with erosive gastroesophageal reflux disease (GERD). After subjects provide written consent to participate in the trial, a screening test is conducted. If subjects are taking medications that may affect the gastric mucosa at the time of screening, an upper gastrointestinal endoscopy is performed after a two-week washout period (except for potassium-competitive acid suppressants (P-CABs) or proton pump inhibitors (PPIs), which require a four-week washout period). Subjects who meet the inclusion / exclusion criteria based on the screening test results are randomly assigned in a 1:1:1 ratio to study group 1, study group 2, or the control group. The study is stratified by grade (A, B, C, D) based on the LA classification determined by upper gastrointestinal endoscopy. Randomized subjects receive the investigational drug once daily for four weeks according to their assigned treatment group. Study subjects will receive the investigational drug for four weeks and then visit the study site for an upper gastrointestinal endoscopy to assess whether they have recovered. Subjects who have recovered will undergo a safety follow-up (F / U) two weeks later. Study subjects who have not recovered will receive the investigational drug for another four weeks (for a total of eight weeks of treatment) and then visit the study site for an upper gastrointestinal endoscopy. Then, regardless of whether they have recovered, they will undergo a safety follow-up (F / U) two weeks later.

[0189] 3. Dosage, duration and method of administration

[0190] A. Dosage

[0191] -Study drug 1: JP-1366, 2 capsules of 5 mg (zastaprazan citrate salt 10 mg)

[0192] -Study drug 2: JP-1366, 20 mg 1 capsule (zastaprazan citrate salt 20 mg)

[0193] -Comparator: esomeprazole magnesium trihydrate 44.5 mg (esomeprazole 40 mg, one Nexium 40 mg tablet)

[0194] B. Administration period

[0195] Study duration per study subject: up to 14 weeks

[0196] -Screening period: 15 days or 29 days

[0197] -Duration of administration: 4 weeks (or 8 weeks)

[0198] -Safety Follow-Up (F / U) Period: 2 weeks after the last dose of investigational drug

[0199] C. Administration method

[0200] Depending on the treatment group to which you are randomly assigned, you will receive the clinical trial drug for 4 weeks (or 8 weeks) from the day you are provided with the drug. * ) should be administered orally once daily on an empty stomach at as regular a time as possible. * Only study subjects whose mucosal defects have not healed after 4 weeks of treatment with the investigational drug will be given an additional 4-week treatment period.

[0201] 4. Efficacy evaluation variables

[0202] A. Primary efficacy evaluation variables:

[0203] Cumulative healing rate (%) of mucosal defects up to 8 weeks after administration of the clinical trial drug

[0204] * Endoscopy of the upper gastrointestinal tract reveals that the erosions have resolved into normal mucosa

[0205] A. Secondary efficacy evaluation variables:

[0206] [1] Healing rate (%) of mucosal defects up to 4 weeks after administration of the clinical trial drug

[0207] [2] Evaluation of symptoms using the subject diary

[0208] A. Evaluation of symptoms (heartburn, acid reflux, heartburn and acid reflux) within 24 hours after administration of the investigational drug

[0209] B. Evaluation of symptoms (heartburn, acid reflux, heartburn and acid reflux) for 7 days after administration of the investigational drug

[0210] C. The date of achieving a complete response (CR) (7-day absence of heartburn and acid reflux) after administration of the investigational drug.

[0211] D. Percentage of symptom-free days (daytime, nighttime, daytime and nighttime) at 4 and 8 weeks after administration of the investigational drug product (heartburn, acid reflux, heartburn and acid reflux)

[0212] [3] Changes in the frequency and severity of each major symptom at 4 and 8 weeks after administration of the clinical trial drug compared to baseline in the Gastroesophageal Reflux Disease Symptom Scale (RDQ)

[0213] [4] Evaluation of quality of life (GERD-HRQL): Change in total score at 4 and 8 weeks after administration of the clinical trial drug compared to baseline

[0214] 5. Safety Assessment Variables

[0215] (1) Abnormal reaction

[0216] (2) Signs of vitality

[0217] (3) Experimental inspection

[0218] (4) Electrocardiogram (12-lead electrocardiogram)

[0219] (5) Physical examination

[0220] 6.Statistical analysis method

[0221] A. Primary efficacy evaluation variables

[0222] Cumulative healing rate (%) of mucosal defects up to 8 weeks after administration of the clinical trial drug

[0223] The proportion of study subjects whose erosions resolved to normal mucosa by week 8 after the first administration of the investigational drug will be presented for each treatment group, along with two-sided 95% confidence intervals. To compare each study group with the control group (JP-1366 10 mg vs. Nexium tablets 40 mg, JP-1366 20 mg vs. Nexium tablets 40 mg), the lower limit of each two-sided 95% confidence interval will be calculated using the Cochran-Mantel-Haenszel method, adjusted for the stratification factors of baseline LA grade (A, B, C, D).

[0224] B. Secondary efficacy evaluation variables

[0225] [1] Healing rate (%) of mucosal defects up to 4 weeks after administration of the clinical trial drug

[0226] The proportion of study subjects whose erosions resolved to normal mucosa by week 4 after the first administration of the investigational drug will be presented for each treatment group, along with the two-sided 95% confidence interval. To compare each study group with the control group (JP-1366 10 mg vs. Nexium tablets 40 mg, JP1366 tablets 20 mg vs. Nexium tablets 40 mg), the lower limit of each two-sided 95% confidence interval will be calculated using the Cochran-Mantel-Haenszel method, adjusted for the stratification factors of baseline LA grade (A, B, C, D).

[0227] [2] Evaluation of symptoms using the subject diary

[0228] A. Evaluation of symptoms (heartburn, acid reflux, heartburn and acid reflux) within 24 hours after administration of the investigational drug: Comparison of the mean symptom (heartburn, acid reflux, heartburn and acid reflux) ratings within 24 hours after the first administration of the investigational drug for each study group compared to the control group will be analyzed using an analysis of covariance (ANCOVA) model with baseline LA grade (A, B, C, D) as the covariate.

[0229] B. Symptom (heartburn, acid reflux, heartburn and acid reflux) assessments for 7 days after administration of the investigational drug: Comparison of each study group compared to the control group for the mean symptom (heartburn, acid reflux, heartburn and acid reflux) assessments for 7 days after the first administration of the investigational drug will be analyzed using an analysis of covariance (ANCOVA) model with baseline LA grade (A, B, C, D) as the covariate.

[0230] C. Date of achieving CR (7-day resolution of heartburn and acid reflux) after administration of the clinical trial drug: CR (7-day resolution of heartburn and acid reflux) was defined as a symptom score of 0 for 7 consecutive days after the first administration of the clinical trial drug, and the event was determined based on the first CR. If there was no CR, the patient was treated as having discontinued treatment. Kaplan-Meier plots and median values ​​with corresponding two-sided 95% confidence intervals were presented for each treatment group. Comparisons of each study group with the control group were performed using a stratified log-rank test with baseline LA grade adjusted for stratification factors.

[0231] D. Percentage of symptom-free days (daytime, nighttime, daytime and nighttime) at 4 and 8 weeks after administration of the investigational drug: Comparison of each study group compared to the control group for the percentage of symptom-free days (heartburn, acid reflux, heartburn and acid reflux) at 4 and 8 weeks after initial administration of the investigational drug for daytime, nighttime, daytime and nighttime, respectively, will be analyzed using an analysis of covariance (ANCOVA) model with baseline LA grade (A, B, C, D) as the covariate.

[0232] [3] Gastroesophageal Reflux Disease Symptom Scale (RDQ)

[0233] Comparison of each test group with the control group for the change in frequency and severity of each main symptom after 4 and 8 weeks of treatment compared to baseline will be performed using an analysis of covariance (ANCOVA) model with baseline LA grade (A, B, C, D) as the covariate. The same statistical analysis as above will be performed on the change in the final result excluding baseline compared to baseline.

[0234] [4] Quality of life assessment (GERD-HRQL)

[0235] The change in the total quality of life score after 4 and 8 weeks of treatment compared to baseline was compared between each study group and the control group using an analysis of covariance (ANCOVA) model with baseline LA grade (A, B, C, D) as the covariate. The same statistical analysis as above was performed on the change in the final result excluding baseline compared to baseline.

[0236] C. Safety evaluation variables

[0237] For study subjects who experienced at least one abnormal reaction (or abnormal drug reaction), the number of events and incidence rate, along with their two-sided 95% confidence intervals, will be presented for each treatment group. A chi-square test or Fisher's exact test will be performed to examine whether there was a difference in the incidence rate of abnormal reactions (or abnormal drug reactions) between the control group and each study group. Furthermore, the latest version of the ICH Medical Dictionary for Regulatory Activities (MedDRA) will be used to present the data, coded by system organ class (SOC) and preferred term (PT). Serious abnormal reactions, abnormal reactions resulting in the discontinuation of administration of the investigational drug, and abnormal reactions resulting in death will also be summarized by system organ class (SOC) and preferred term (PT) using the latest version of MedDRA. For experimental tests, vital signs, and electrocardiograms (12-lead ECGs), descriptive statistics (number of subjects, mean, standard deviation, median, minimum, maximum) for each visit and for the amount of change compared to baseline will be presented for continuous data, and contingency tables will be created for categorical data. For experimental tests and electrocardiograms (12-lead ECGs), data will be summarized for each evaluation time point in the form of a shift table, separated into normal or clinically insignificant abnormalities (normal or abnormal NCS) and clinically significant abnormalities (normal CS) to confirm changes in normality or non-normality compared to baseline after administration of the clinical trial drug. For physical examinations, a list of subjects who were normal or clinically insignificant abnormalities (abnormal NCS) at baseline but showed a change to clinically significant abnormalities (abnormal CS) after administration of the clinical trial drug will be presented.

[0238] 7. Phase II clinical results

[0239] A. Check whether symptoms have improved

[0240] Evaluation of all symptoms (heartburn, acid reflux, heartburn / acid reflux) within 24 hours and for 7 days after administration of the clinical trial medications showed a tendency for all symptoms to improve within 24 hours and for 7 days after administration of the clinical trial medications, Study Drugs 1 and 2.

[0241] B. Confirmation of healing rate

[0242] (1) Helicobacter pylori (H. pylori) positive group (infected group)

[0243] In the JP-1366 20 mg (zastaprazan 20 mg) administration group, a 100% cure effect was achieved at both 4 and 8 weeks, while Nexium 40 mg achieved an 87.5% cure (see Table 5).

[0244] [Table 7]

[0245] (2) Helicobacter pylori (H. pylori)-negative group

[0246] In the JP-1366 20 mg (zastaprazan 20 mg) group, it was found that the same effect was achieved as that of Nexium 40 mg (see Table 6). This indicates that clinical trials have confirmed that zastaprazan can achieve the same effect as Nexium 40 mg, the control group, even at a significantly lower dose.

[0247] [Table 8]

[0248] (3) Overall cure rate

[0249] Considering the results of the Helicobacter pylori (H. pylori)-positive group (infected group) and the Helicobacter pylori (H. pylori)-negative group, the overall cure rate was 93.75% (45 / 48 subjects) in the JP-1366 10 mg group, 91.49% (43 / 47 subjects) in the JP-1366 20 mg group, and 89.80% (44 / 49 subjects) in the esomeprazole 40 mg group.

[0250] (4) Conclusion

[0251] Nexium 40 mg showed a higher erosion healing rate in Helicobacter pylori (H. pylori)-negative patients than in H. pylori-positive patients, and it was found that the pharmaceutical composition of the present invention is effective in treating gastroesophageal reflux disease and / or peptic ulcers regardless of whether or not the patient is infected with H. pylori, and in fact tends to be more effective in patients infected with H. pylori. This is believed to be due to the eradication effect of zastaprazan itself in the pharmaceutical composition of the present invention.

[0252] Example 3. Anti-Helicobacter pylori (H. pylori) efficacy test (Phase III clinical trial) in patients with erosive gastroesophageal reflux disease - Confirmation of the eradication effect of zastaprazan itself

[0253] The number of subjects was increased and a Phase III clinical trial was conducted. Specifically, the drug was orally administered once daily, regardless of meals, at as regular a time as possible, for a total of four weeks according to the randomly assigned treatment group, and the cumulative healing rate of mucosal breaks in test subjects who were Helicobacter pylori (H. pylori) positive (infected) was confirmed.

[0254] [Table 9]

[0255] Per Protocol Set (PPS)

[0256] Analysis of the PPS, the primary analysis group of this clinical trial, showed that 26 test subjects in the test group and 22 in the control group tested positive for Helicobacter pylori (H. pylori). Four weeks after administration of the clinical trial drug, the proportion of test subjects whose mucosal defects had healed on endoscopic examination was 100.00% (26 / 26 subjects) in the test group and 81.82% (18 / 22 subjects) in the control group, showing a statistically significant difference between the two treatment groups (p=0.0214).

[0257] Full Analysis Set (FAS)

[0258] FAS analysis showed that 28 test subjects in the test group tested positive for Helicobacter pylori (H. pylori), and 25 in the control group. The percentage of test subjects whose mucosal defects had healed on endoscopic examination four weeks after administration of the clinical trial drug was 96.43% (27 / 28 subjects) in the test group and 80.00% (20 / 25 subjects) in the control group, demonstrating a significant difference in efficacy compared to the control group at four weeks.

[0259] [Table 10]

[0260] [Table 11]

[0261] Example 4. Evaluation of drug interactions between zastaprazan (JP-1366), amoxicillin, and clarithromycin in healthy adult volunteers

[0262] 1. Purpose of clinical trials

[0263] The purpose of this clinical trial was to evaluate the effect of concomitant administration of amoxicillin and clarithromycin on the pharmacokinetics, safety, and tolerability of JP-1366 in healthy adult volunteers, and the effect of JP-1366 on the pharmacokinetics, safety, and tolerability of amoxicillin and clarithromycin. The target number of study subjects was 24, and the clinical trial was conducted in healthy adults using a randomized, fasting, 3-way, repeated-dose, crossover design.

[0264] 2. Study drug and administration period

[0265] A. Test drug 1: JP-1366 capsules 20 mg

[0266] Manufacturer: Daiichi Pharmaceutical

[0267] Dose: JP-1366 20mg

[0268] Route of administration: Oral

[0269] B. Test drug 2: Kimoxin capsules 500 mg

[0270] Manufacturer: Ryukan Yoko Co., Ltd.

[0271] Dosage: Amoxicillin hydrate 500 mg

[0272] Route of administration: Oral

[0273] C. Test drug 3: Claricid film-coated tablets 500 mg

[0274] Dose: Clarithromycin 500 mg

[0275] Manufacturer: Korea Aboat Co., Ltd.

[0276] Route of administration: Oral

[0277] D. Medication period

[0278] Repeated administration twice daily for 5 days for each period

[0279] 3. Selection and classification of clinical trial subjects

[0280] A total of 24 study subjects participated in this clinical trial and received the investigational drug. All subjects completed all study procedures and visits according to the clinical trial protocol. Therefore, pharmacokinetic and safety evaluations were conducted on the 24 study subjects. Pharmacokinetic statistical analysis was conducted in Part A and Part B.

[0281] Part A: One capsule of JP-1366 20 mg, twice daily for 5 days (T1) or one capsule of JP-1366 + two capsules of amoxicillin 500 mg + one tablet of clarithromycin 500 mg, twice daily for 5 days (T3)

[0282] Part B: Two amoxicillin 500 mg capsules + one clarithromycin 500 mg tablet, twice daily for 5 days (T2) or one JP-1366 20 mg capsule + two amoxicillin 500 mg capsules + one clarithromycin 500 mg tablet, twice daily for 5 days (T3).

[0283] 4.Results

[0284] [Part A]

[0285] The pharmacokinetic evaluation results of JP-1366 are as follows:

[0286] [Table 12]

[0287] (In Table 9 above, T1 means one capsule of JP-1366 20 mg, and T3 means one capsule of JP-1366 20 mg + two capsules of amoxicillin 500 mg + one tablet of clarithromycin 500 mg.)

[0288] In Part A, JP-1366 20mg 1 capsule was administered twice daily for 5 days (T1) or JP-1366 1 capsule + amoxicillin 500mg 2 capsules + clarithromycin 500mg 1 tablet was administered twice daily for 5 days (T3). max,ss , AUC T The effect of co-administration with amoxicillin and clarithromycin on the pharmacokinetics of JP-1366 was evaluated by calculating the 90% confidence interval of the geometric mean ratio (T3 / T1) using the primary evaluation variable. max,ss , AUC T The 90% confidence interval of the geometric mean ratio (T3 / T1) exceeded the upper limit of the range of 0.8-1.25, indicating that C max,ss is about 1.8 times higher, AUC T was approximately 2.4 times higher.

[0289] [Part B]

[0290] The pharmacokinetic evaluation results of amoxicillin are as follows:

[0291] [Table 13]

[0292] (In Table 10 above, T2 means two 500 mg amoxicillin capsules and one 500 mg clarithromycin tablet, and T3 means one 20 mg JP-1366 capsule, two 500 mg amoxicillin capsules, and one 500 mg clarithromycin tablet.)

[0293] In Part B, two capsules of amoxicillin 500 mg plus one tablet of clarithromycin 500 mg were administered twice daily for five days (T2) or one capsule of JP-1366 20 mg plus two capsules of amoxicillin 500 mg plus one tablet of clarithromycin 500 mg were administered twice daily for five days (T3). max,ss , AUC T The effect of co-administration of JP-1366 on the pharmacokinetics of amoxicillin and clarithromycin was evaluated by calculating the 90% confidence interval of the geometric mean ratio (T3 / T2) using the primary evaluation variable. T The 90% confidence interval of the geometric mean ratio (T3 / T2) was within 0.8-1.25, but the C max,ss The 90% confidence interval of the geometric mean ratio (T3 / T2) was outside the range of 0.8-1.25, indicating that the C of amoxicillin was significantly higher when T3 was administered than when T2 was administered. max,ss was about 20% lower.

[0294] The pharmacokinetic evaluation results of clarithromycin are as follows:

[0295] [Table 14]

[0296] Clarithromycin C max,ss The 90% confidence interval of the geometric mean ratio (T3 / T2) was within 0.8-1.25, but the AUC T The 90% confidence interval of the geometric mean ratio (T3 / T2) was outside the range of 0.8-1.25, and the AUC of clarithromycin was significantly higher when T3 was administered than when T2 was administered.T When comparing the combined administration of amoxicillin, clarithromycin, and JP-1366 with the administration of amoxicillin or clarithromycin alone, the drug exposure was less than two-fold, indicating that there was no clinically significant pharmacokinetic drug interaction.

[0297] Example 5. Anti-Helicobacter pylori (H. pylori) in vitro efficacy test - Confirmation of eradication effect of combined administration of Zastaprazan (JP-1366) and clarithromycin

[0298] 1. Purpose of the test

[0299] The purpose of this study was to confirm that zastaprazan (JP-1366) had antibacterial activity, unlike omeprazole and fexprazan, as a result of primary antibacterial activity tests. Prior to confirming the effect of zastaprazan (JP-1366) on enhancing the antibacterial activity of clarithromycin, which is used in triple therapy, this additional study was conducted under in vitro experimental conditions to confirm the enhancing effect of antibacterial activity against susceptible strains when zastaprazan (JP-1366) is used in combination with clarithromycin in double therapy.

[0300] 2. Test Substances

[0301] A. Drugs

[0302] The drugs used in the in vitro experiments are as shown in Table 12 below.

[0303] [Table 15]

[0304] A. Reagents

[0305] The reagents used in the in vitro experiments are as shown in Table 13 below.

[0306] [Table 16]

[0307] C. Bacterial strain

[0308] Helicobacter pylori (H. pylori) SS1 (mouse colonizing strain): Also known as the Sydney strain, this strain is CagA-positive and VacA-positive and has been shown to infect and colonize C57BL / 6 mice, and is used in animal experiments.

[0309] D. Equipment

[0310] The equipment used in the in vitro experiments is as shown in Table 14 below.

[0311] [Table 17]

[0312] 3. Preparation of Culture Medium and Test Substances

[0313] A. Culture medium

[0314] BHI is prepared by adding 7% hemolyzed horse blood (Oxoid, Basingstoke, Hampshire, UK), 0.4% Isovitalex, and 1.5-2% Bacto-agar (Difco, Sparks, Maryland, USA).

[0315] a. Culture medium for MIC measurement

[0316] Mueller-Hinton broth (MH) (Difco, Sparks, Maryland, USA) [w / 7% differentiation medium (Sigma-Aldrich, St. Louis, Missouri, USA), 0.4% Isovitalex (Baltimore Biological Laboratory, Sparks, Maryland, USA)] was used to examine synergistic effects. Mueller-Hinton broth (MH) medium prepared as described above was supplemented with JP-1366 at a concentration half the MIC value of zastaprazan (JP-1366), and this was used as the basal medium for MIC measurements.

[0317] C. Preparation of test substances

[0318] Zastaprazan (JP-1366) was supplied as a product prepared at a concentration of 10 mM in dimethyl sulfoxide (DMSO) solvent, and clarithromycin was prepared at a concentration of 5 mg / mL in DMSO solvent.

[0319] 4. In-vitro efficacy testing

[0320] A. Zastaprazan (JP-1366) for the treatment of Helicobacter pylori (H. pylori) ) MIC measurement for SS1

[0321] Antibiotic susceptibility testing was performed using MH agar (7% horse serum, 0.4% Isovitalex, 1.5–2% agar) in a 6-well plate, with a maximum medium volume of 2 mL. JP-1366 was diluted in six steps, with the highest concentration at 32 μg / mL, the maximum MBC, and then MIC measurements were performed. Helicobacter pylori (H. pylori) stored in a deep freezer (below -70°C) was inoculated onto BHI agar (with 7% lysed horse blood, 0.4% Isovitalex) and cultured at 37°C under microaerophilic conditions (Oxoid CampyGene™ gas pack) for 3 days, after which it was subcultured onto new medium. The cultured bacteria were harvested, suspended in PBS, and then measured at a concentration of 0.5 McFarland units (1.5 x 10 8After suspending the bacteria at a concentration of 0.01 CFU / mL, 2 μL of the suspension is inoculated onto a solid medium, and the medium is cultured under microaerobic conditions for 3 days. The lowest concentration at which no growth can be visually confirmed is determined as the MIC.

[0322] B. Zastaprazan (JP-1366) enhances the antibacterial activity of clarithromycin against Helicobacter pylori (H. pylori)

[0323] Antibiotic susceptibility testing will be performed by microdilution in accordance with CLSI guidelines.

[0324] Antibiotic susceptibility testing was performed using MH broth (7% horse serum, 0.4% Isovitalex), with the susceptibility test medium for zastaprazan (JP-1366) prepared. A final medium volume of 200 μL was used in a 48-well plate, with the zastaprazan (JP-1366) concentration set at half the MIC value of zastaprazan (JP-1366). Using the medium prepared in this way, clarithromycin was serially diluted in 16 steps, starting with a maximum concentration of 16 μg / mL. Wells containing only medium without antibiotics served as the negative control, while wells containing only bacteria inoculated in medium without antibiotics served as the positive control. Helicobacter pylori (H. pylori) stored in a deep freezer (below -70°C) was inoculated onto BHI agar (w / 7% hemolyzed horse blood, 0.4% Isovitalex) and cultured at 37°C under microaerophilic conditions (Oxoid CampyGene™ gas pack) for 3 days, after which it was subcultured onto a new medium. The cultured bacteria were harvested and suspended in PBS, and then subcultured onto a new medium at 5x10 5Each well was inoculated with a CFU / mL concentration of bacteria, and the sample was incubated at 37°C under microaerophilic conditions of 5% O2, 10% CO2, and 85% N2 for 3 days. The lowest concentration at which no bacterial growth was observed was determined as the MIC. Next, 10 μL of the culture medium from each well was spotted onto antibiotic-free BHI agar (7% hemolyzed horse blood, 0.4% Isovitalex) and incubated at 37°C under microaerophilic conditions (Oxoid CampyGene™ gas pack) for 3 days. The lowest concentration at which no bacterial growth was observed was determined as the minimum bactericidal concentration (MBC).

[0325] 5. Experimental Results

[0326] The efficacy of JP-1366 in increasing the antibacterial activity of clarithromycin against Helicobacter pylori (H. pylori) through this test will be determined by one of the following methods.

[0327] 1) When the drug is co-administered with clarithromycin, the MIC (or MBC) of clarithromycin decreases.

[0328] 2) When antibiotic-resistant strains are treated with clarithromycin at a specific concentration at which the bacteria grow, the percentage of strains in which cell growth inhibition is observed increases.

[0329] As shown in Table 15, when clarithromycin was added to a medium containing zastaprazan (JP1366) at half the MIC concentration, the MBC was reduced by half. To further confirm this effect, additional experiments were conducted on resistant strains (see Example 6 below).

[0330] [Table 18]

[0331] Example 6. In vitro efficacy test against Helicobacter pylori (H. pylori) - Confirmation of eradication effect of combined administration of Zastaprazan (JP-1366), amoxicillin, and clarithromycin

[0332] 1. Purpose of the test

[0333] The purpose of this study was to conduct research under in vitro experimental conditions to confirm the effectiveness of triple therapy with zastaprazan (JP-1366), amoxicillin, and clarithromycin in enhancing antibacterial activity against resistant strains of bacteria.

[0334] 2. Test Substances

[0335] The bacterial strains used in this study are as follows:

[0336] -Helicobacter pylori (H. pylori) ATCC43503: Standard strain for antibiotic susceptibility testing

[0337] -Antibiotic-resistant clinical isolates: Provided by the Difficult-to-Cultivate Pathogen Resource Bank, Gyeongsang National University Hospital, Republic of Korea.

[0338] [Table 19]

[0339] 3. Preparation of Culture Medium and Test Substances

[0340] The culture medium, the medium for MIC measurement, and the test substance were prepared in the same manner as described in Example 5 above.

[0341] 3.In-vitro efficacy testing

[0342] A. Confirmatory study of MIC and MBC of Zastaprazan (JP-1366) against 10 strains of bacteria

[0343] Antibiotic susceptibility testing will be performed by the microdilution method in accordance with CLSI (Clinical and Laboratory Standards Institute) guidelines.

[0344] Amoxicillin and clarithromycin were diluted to 128μg / mL, amoxicillin and clarithromycin were mixed at a 1:1 ratio to 64μg / mL, and JP-1366, omeprazole, and fexprazan were diluted 2-fold with a maximum concentration of 256μg / mL, but in 12 steps. A test tube containing only culture medium and no antibiotics was inoculated with bacteria to serve as the positive control, and a test tube containing only culture medium without antibiotics or bacteria was used as the negative control. Helicobacter pylori (H. pylori) stored in a deep freezer at -70°C is thawed and inoculated onto BHI agar (w / 7% hemolyzed horse blood, 0.4% Isovitalex) and cultured at 37°C under microaerophilic conditions of 5% O2, 10% CO2, and 85% N2 gas for 3 days, after which it is subcultured onto new medium. The cultured bacteria are harvested and suspended in sterilized PBS, and then subcultured at 5x10 5 Test tubes were inoculated at a concentration of cfu / mL, and incubated at 37°C under microaerophilic conditions of 5% O2, 10% CO2, and 85% N2 for three days. The lowest concentration at which no bacterial growth was observed was determined as the MIC. Ten microliters of the culture medium from each test tube was then spotted onto antibiotic-free BHI agar (with 7% hemolyzed horse blood, 0.4% Isovitalex) and incubated at 37°C under microaerophilic conditions for three days. The lowest concentration at which no bacterial growth was observed was determined as the minimum bactericidal concentration (MBC).

[0345] B. Zastaprazan (JP-1366) enhances the antibacterial activity of amoxicillin and clarithromycin against Helicobacter pylori (H. pylori)

[0346] Antibiotic susceptibility testing will be performed using the microdilution method in accordance with CLSI guidelines.

[0347] Antibiotic susceptibility testing was performed using MH broth (7% horse serum, 0.4% Isovitalex). Three susceptibility test media containing zastaprazan (JP-1366), omeprazole, and fexprazan were prepared. Tests were performed in 48-well plates with a final medium volume of 200 μL. The concentrations of zastaprazan (JP-1366), fexprazan, and omeprazole in the media were standardized to the zastaprazan (JP-1366) MIC (or, if the MIC was difficult to determine, the highest concentration at which the bacteria survived after MBC determination) for each clinical isolate. Using the media prepared in this way, amoxicillin and clarithromycin (mixed at a 1:1 ratio) were serially diluted 2-fold, starting at 64 μg / mL, for a total of 12 dilutions. The negative control group consisted of wells containing only medium without antibiotics, while the positive control group consisted of wells inoculated with bacteria in medium without antibiotics. Helicobacter pylori (H. pylori) was inoculated onto BHI agar (w / 7% hemolyzed horse blood, 0.4% Isovitalex) and cultured at 37°C under microaerophilic conditions (Oxoid CampyGene™ gas pack) for 3 days, after which it was subcultured onto new medium. The cultured bacteria were harvested and suspended in PBS, and then 5x10 5 Each well was inoculated with a CFU / mL sample and incubated at 37°C under microaerophilic conditions of 5% O2, 10% CO2, and 85% N2 for 3 days. The lowest concentration at which no bacterial growth was observed was determined as the MIC. Next, 10 μL of the culture medium from each well was spotted onto antibiotic-free BHI agar (7% hemolyzed horse blood, 0.4% Isovitalex) and incubated at 37°C under microaerophilic conditions (Oxoid CampyGene™ gas pack) for 3 days. The lowest concentration at which no bacterial growth was observed was determined as the minimum bactericidal concentration (MBC). The experimental level was monitored by amoxicillin susceptibility testing of HP43504.

[0348] C. Number of antibiotic combinations

[0349] As shown in Table 17 below, a total of three antibiotics are combined and susceptibility tests for amoxicillin and clarithromycin are performed against 10 strains of bacteria.

[0350] [Table 20]

[0351] The efficacy of the drugs (zastaprazan (JP-1366), omeprazole, and fexprazan) in increasing the antibacterial activity of amoxicillin and clarithromycin against Helicobacter pylori (H. pylori) in this study will be determined by one of the following methods.

[0352] 1) When drugs are co-administered with amoxicillin and clarithromycin, the MIC (or MBC) of amoxicillin and clarithromycin decreases.

[0353] 2) When antibiotic-resistant strains are treated with amoxicillin and clarithromycin at a specific concentration at which the bacteria grow, the percentage of strains in which cell growth inhibition is observed increases.

[0354] Although specific portions of the present invention have been described in detail above, it will be apparent to those skilled in the art that such specific descriptions are merely preferred embodiments and do not limit the scope of the present invention. Therefore, the true scope of the present invention should be defined by the appended claims and their equivalents.

Claims

1. A composition for eradicating Helicobacter pylori, comprising zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, and amoxicillin, a pharmaceutically acceptable salt thereof, or a hydrate thereof.

2. A composition for eradicating Helicobacter pylori, comprising zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, and clarithromycin or a pharmaceutically acceptable salt thereof.

3. A composition for eradicating Helicobacter pylori, comprising zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, amoxicillin, a pharmaceutically acceptable salt thereof, or a hydrate thereof, and clarithromycin or a pharmaceutically acceptable salt thereof.

4. The composition for eradicating Helicobacter pylori according to any one of claims 1 to 3, wherein the pharmaceutically acceptable salt of zastaprazan is zastaprazan citrate.

5. The Helicobacter pylori eradication composition according to any one of claims 1 to 3, comprising 5 to 40 mg of zastaprazan citrate salt.

6. The Helicobacter pylori eradication composition according to any one of claims 1 to 3, comprising 100 mg to 1000 mg of amoxicillin, a pharmaceutically acceptable salt thereof, or a hydrate thereof.

7. 4. The Helicobacter pylori eradication composition according to claim 2, wherein the eradication composition contains 100 mg to 1000 mg of clarithromycin or a pharmaceutically acceptable salt thereof.

8. The Helicobacter pylori eradication composition according to any one of claims 1 to 3, wherein the eradication composition is administered once to three times a day.

9. The Helicobacter pylori eradication composition according to any one of claims 1 to 3, wherein the eradication composition is formulated into a solid oral preparation.

10. 10. The composition for eradicating Helicobacter pylori according to claim 9, wherein the solid oral formulation is any one of tablets, film-coated tablets, capsules, powders, granules, pills, lozenges, oral jellies, and orally dissolving films.

11. A composition for treating infections caused by Helicobacter pylori, comprising zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, and amoxicillin, a pharmaceutically acceptable salt thereof, or a hydrate thereof.

12. A composition for treating an infection caused by Helicobacter pylori, comprising zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, and clarithromycin or a pharmaceutically acceptable salt thereof.

13. A composition for treating an infection caused by Helicobacter pylori, comprising zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, amoxicillin, a pharmaceutically acceptable salt thereof, or a hydrate thereof, and clarithromycin or a pharmaceutically acceptable salt thereof.

14. A method for eradicating Helicobacter pylori, comprising the step of administering to a subject in need thereof a pharmaceutically effective amount of a composition comprising a therapeutically effective amount of zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, and clarithromycin or a pharmaceutically acceptable salt thereof.

15. A method for eradicating Helicobacter pylori, comprising the step of administering to a subject in need thereof a pharmaceutically effective amount of a composition comprising a therapeutically effective amount of zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, amoxicillin, a pharmaceutically acceptable salt thereof, or a hydrate thereof, and clarithromycin or a pharmaceutically acceptable salt thereof.

16. Use of a pharmaceutical composition comprising zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, and clarithromycin or a pharmaceutically acceptable salt thereof, for eradicating Helicobacter pylori.

17. Use of a pharmaceutical composition comprising zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, amoxicillin, a pharmaceutically acceptable salt thereof, or a hydrate thereof, and clarithromycin or a pharmaceutically acceptable salt thereof, for eradicating Helicobacter pylori.

18. Use of a composition comprising zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, and clarithromycin or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for eradicating Helicobacter pylori.

19. Use of a composition comprising zastaprazan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, amoxicillin, a pharmaceutically acceptable salt thereof, or a hydrate thereof, and clarithromycin or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for eradicating Helicobacter pylori.

Images